Contribution of itraconazole metabolites to inhibition of CYP3A4 in vivo

Abstract

Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

Figure 1

Structures of itraconazole (ITZ) and its metabolites hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ) and N-desalkyl-itraconazole (ND-ITZ). * indicates a chiral center.

Figure 2

Selected ion chromatograms from a representative subject plasma showing the detection of itraconazole (ITZ), hydroxy-ITZ (OH-ITZ), keto-ITZ and N-desalkyl-ITZ (ND-ITZ) in vivo after administration of 100 mg itraconazole in oral solution.

Figure 3

Mean plasma concentration (± SD) versus time curves for itraconazole (a), hydroxy-itraconazole (OH-ITZ) (b), keto-itraconazole (keto-ITZ) (c) and N-desalkyl-itraconazole (ND-ITZ) (d) on day 1 (solid boxes) and day 7 (open circles) of the study in the six volunteers. The symbols are the mean values of the six subjects and the bars show standard deviation. For keto-ITZ only two subjects had quantifiable plasma concentrations at 24 hours after the first dose and for ND-ITZ only one subject had quantifiable plasma concentrations at 0.5 hours after first ITZ dose. For calculation of the mean concentration other plasma concentrations were considered to be zero.

Figure 4

The predicted time-course of CYP3A4 inhibition by ITZ and its metabolites on study day 1 (A) and day 7 (B) and the relative contribution of each inhibitory species to the overall CYP3A4 inhibition on study day 1 (C) and day 7 (D). The insets in A and B depict the time course of the total predicted fold decrease in the intrinsic clearance of a CYP3A4 substrate when ITZ and its metabolites are all used for prediction. Closed diamonds show ITZ, open diamonds OH-ITZ, open boxes keto-ITZ and crosses ND-ITZ.